Introduction
According to the Global Burden of Disease Study 2019, 12 million people suffer from stroke, and 7 million people die from stroke each year.[1] The total number of stroke cases has increased continuously since 1990, reaching an estimated 101 million people as of 2019.[1] Approximately 1 in 4 people worldwide have a lifetime risk of developing a stroke after the age of 25.[2] Patients who have experienced prior stroke or transient ischemic attack (TIA) events are at a very high risk of experiencing recurrent stroke events.[3,4] Stroke survivors also face increased risks of cognitive decline[5,6] and other types of cardiovascular disease (eg, coronary heart disease[4,7] and peripheral vascular disease).
Although stroke risks have been associated with both modifiable and non-modifiable risk factors, the 10 most commonly identified major modifiable risk factors (high blood pressure (BP), current smoking, high waist-to-hip ratio, unhealthy dietary habits, physical inactivity, diabetes mellitus, excessive alcohol drinking, psychosocial factors, cardiac disease, and dyslipidemia) accounted for up to 90% of the population attributable risk for stroke development according to the INTERSTROKE study.[8] High BP is a major modifiable risk factor associated with an estimated population attributable risk for stroke development of 48%. Thus, BP lowering is likely to represent an important strategy for stroke prevention.
Many randomized controlled trials have demonstrated that treatments that effectively lower BP are among the most beneficial prevention strategies for both primary and secondary stroke prevention.[9–11] We review the results of those randomized controlled trials that have examined the beneficial effects of reducing BP to prevent recurrent stroke.
Evidence from randomized trials
Several randomized trials have demonstrated that BP-lowering medications decrease the risks of initial stroke.[9,10] However, before the results of the PROGRESS trial were reported, limited evidence was available regarding the beneficial effects of BP-lowering treatment for recurrent stroke prevention among patients with prior stroke or TIA events. In the mid-1990s, some evidence of the beneficial effects of reducing BP for preventing stroke was provided by the preliminary publication of a randomized controlled trial investigating the effects of diuretics among 5665 patients with prior stroke or TIA (PATS) events[12] and an individual patient data systematic review and meta-analysis of randomized controlled trials (INDANA Project) including a subgroup of patients with prior stroke history.[13] The PATS trial showed that use of a diuretic (indapamide) reduced the incidence of recurrent stroke (relative risk reduction (RRR): 27%; 95% confidence interval (95% CI): 11%–40%), although the complete data for the PATS trial was not published internationally.[12] The INDANA Project suggested that BP reductions prevented recurrent stroke incidence by 28% (95% CI: 15%–39%) among patients with hypertension who had prior stroke.[13] Although these findings were promising, they did not provide conclusive evidence to support the beneficial effects of reducing BP among normotensive subjects with prior stroke or TIA.
In 2001, the PROGRESS trial presented evidence showing the clear benefits of reducing BP for the prevention of recurrent stroke.[14,15] PROGRESS was a randomized, parallel-group, double-blinded trial that showed the beneficial effects of BP-lowering treatments across a wide range of patient groups with prior stroke or TIA. A total of 6105 patients with cerebrovascular disease were randomized to receive BP-lowering treatment regimens (an angiotensin-converting enzyme (ACE) inhibitor (perindopril) with or without a diuretic (indapamide)) or appropriate placebo(s). During an average follow-up duration of 3.9 years, the BP-lowering treatments reduced the risk of recurrent stroke by 28% (95% CI: 17%–38%) compared with the placebo-treated control group. PROGRESS trial also showed comparable effect sizes for BP-lowering treatments between patients with hypertension (defined as BP ≥160/90 mmHg, according to the guidelines for hypertension management at that time) and those without hypertension. These findings established the beneficial effects of BP-lowering treatments for patients with a history of stroke/TIA but without hypertension for the first time.
In the PROGRESS trial, the combined use of perindopril and indapamide produced larger reductions in stroke risk (RRR: 43%; 95% CI: 30%–54%) than perindopril only (RRR: 5%; 95% CI: −19% to 23%). The observed increase in the beneficial effects of combination therapy (perindopril + indapamide) for the prevention of recurrent stroke is likely attributable to the larger BP reduction observed for patients on combination therapy (12/5 mmHg) than for patients treated with perindopril only (5/3 mmHg).[14]
Several randomized trials performed after the publication of the PROGRESS trial results have investigated the effects of BP-lowering treatments for the secondary prevention of stroke. The FEVER trial demonstrated a tendency toward recurrent stroke prevention among a subgroup of 2368 patients with prior stroke/TIA (RRR: 18%; 95% CI: −12% to 40%), which was associated with a 4.0/1.8 mmHg reduction in BP, among patients prescribed the calcium channel blocker felodipine.[16] By contrast, the results from PRoFESS trial were less positive.[17] PRoFESS investigated the effects of the angiotensin receptor blocker (ARB) telmisartan among 20,322 participants who had experienced an ischemic stroke within 90 days prior to recruitment. In the ARB group, BP was lowered by 4/2 mmHg, and the risk of recurrent stroke was reduced by 5% (95% CI: −4% to 14%). The non-significant reduction in recurrent stroke incidence observed in the PRoFESS trial may be attributable to the relatively small reduction in BP achieved, the large proportion of included patients with large artery infarction (30%), and the frequent use of ACE inhibitors (37%).
Our meta-analysis of 17 randomized trials comparing active treatment with control (placebo/no treatment) groups, including the PROGRESS, FEVER, and PRoFESS trials, demonstrated the clear benefits of BP-lowering treatments for the secondary prevention of stroke (RRR: 25%; 95% CI: 14%–35%) [Figure 1].[12–14,16–25] Definite evidence is now available to support the recommendation of BP-lowering treatment for reducing the stroke recurrence risk among patients with a history of stroke or TIA.
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Figure 1: Meta-analysis of randomized controlled trials of blood pressure lowering treatments (active
vs. control) for secondary prevention of stroke.
[12–14,16–25] Solid boxes represent estimates of hazard ratio; areas of the boxes are proportional to the inverse variance of the estimates; vertical lines represent 95% CI; diamond represents estimate and 95% CI for overall effects. CI: Confidence interval.
Optimal BP management and target BP levels in the secondary prevention of stroke
The optimal timing for the initiation of BP-lowering treatments differs depending on the type of stroke. For patients with intracerebral hemorrhage, the INTERACT2 trial demonstrated that rapid BP-lowering treatments targeting systolic BP levels <140 mmHg during the acute phase were beneficial for functional recovery.[26] An observational analysis of the INTERACT2 trial also demonstrated the achievement of systolic BP levels of 130 to 139 mmHg (from the hyperacute phase through 7 days after onset) was likely to provide maximum protection.[27] Therefore, the administration of continuous BP-lowering treatments starting in the hyperacute phase and continuing throughout the chronic phase is recommended for patients with intracerebral hemorrhage. By contrast, no definite evidence supports the administration of BP-lowering treatments during the acute phase of ischemic stroke.[28]
Among patients with ischemic stroke, BP-lowering treatments should be considered after the clinical condition is stabilized, and the initiation of BP-lowering treatments for the secondary prevention of ischemic stroke will depend on the characteristics and clinical course of each patient (eg, severity, ischemic stroke subtype, presence/absence of large artery stenosis, and use of endovascular/thrombolytic treatment). The current Japanese guidelines for the management of hypertension recommends the application of BP-lowering treatments, targeting BP levels <130/80 mmHg during the chronic phase (defined as ≥1 month after onset) following ischemic stroke.[29] The initiation of BP-lowering treatment within 1 month after onset appears reasonable for many patients with ischemic stroke.
A subgroup analysis of the PROGRESS trial investigated the effects of BP-lowering treatments for the secondary prevention of stroke according to baseline systolic BP [Figure 2].[30] The BP-lowering regimen consisting of perindopril and indapamide provided comparable reductions in recurrent stroke incidence across 4 subgroups (baseline systolic BP <120, 120–139, 140–159, and ≥160 mmHg; P for homogeneity = 0.5). These findings suggest that BP-lowering therapy is beneficial for the secondary prevention of stroke, regardless of the patients’ BP levels, although more definite evidence remains necessary to verify these findings.
Figure 2: Effects of blood pressure lowering treatments with combination therapy (ACE inhibitor + diuretic) on recurrent stroke by baseline blood pressure: PROGRESS study. Solid boxes represent estimates of hazard ratio for stroke; areas of the boxes are proportional to the inverse variance of the estimates; vertical lines represent 95% CI; diamond represents estimate and 95% CI for overall effect. ACE inhibitor: Angiotensin converting enzyme inhibitor; CI: Confidence interval; SBP: Systolic blood pressure. Reproduced from reference 26 with permission from Wolters Kluwer Health.
With regard to the optimal BP target, several prospective studies have demonstrated linear associations between BP and initial stroke.[31,32] A pooled analysis of prospective studies (Prospective Studies Collaboration) showed that reduced BP levels (down to 115/75 mmHg) are linearly associated with reduced mortality due to stroke.[31] Linear relationships between BP and both fatal and non-fatal strokes were also observed down to 115/75 mmHg in another pooled analysis (Asia Pacific Cohort Studies Collaboration).[32] Some observational studies in patients with a prior stroke/TIA have also suggested the existence of linear associations between BP levels and the recurrence rates of stroke. An observational analysis of a randomized trial showed a linear relationship between BP (down to 130/80 mmHg mmHg) and the recurrence rate of stroke.[33]
A post hoc analysis of the PROGRESS trial demonstrated that the lowest risk of recurrent stroke was observed among patients who achieved BP of 115/75 mmHg [Figure 3].[30] Linear associations were observed for ischemic stroke and intracerebral hemorrhage [Figure 3].[30] By contrast, an observational analysis of the PRoFESS trial demonstrated a slight increase in the occurrence of recurrent stroke among patients who achieved systolic BP levels <120 mmHg,[34] although the modest increase in very low systolic BP levels disappeared after the exclusion of patients within 6 months from stroke onset. These observational data suggest that during the chronic, stable phase following stroke, lower BP levels are continuously related to lower recurrence rates, down to 115/75 mmHg.
Figure 3: Annual rates of ischemic stroke and intracerebral hemorrhage according to achieved follow-up systolic blood pressure levels: PROGRESS study. Solid boxes represent estimates of hazard ratio for stroke; areas of the boxes are proportional to the inverse variance of the estimates; vertical lines represent 95% CI. Reproduced from reference 26 with permission from Wolters Kluwer Health.
New research examining the benefits of reduced BP for the secondary prevention of stroke has been performed during the past decade. Randomized trials have explored the effects of strict BP control targeting lower systolic BP levels, providing the best available evidence regarding the optimal target BP levels among patients with a prior stroke/TIA. The SPS3 trial investigated the effects of strict BP control, targeting systolic BP <130 mmHg, among 3020 patients with symptomatic lacunar infarction.[35] The mean difference in systolic BP between strict BP control group and control group was 11 mmHg. A non-significant reduction in the recurrent stroke risk (RRR: 19%; 95% CI: −3% to 36%) was observed, whereas a significant reduction was observed for intracerebral hemorrhage (RRR: 63%; 95% CI: 5%–85%). The non-significant associations between BP control and total stroke risk observed in the SPS3 trial might be attributable to limited statistical power due to a smaller number of events than expected (277 vs. more than 500 events).
The PAST-BP trial[36] and the pilot PODCAST study[37] also investigated the effects of strict BP control (targeting systolic BP <130 mmHg in PAST-BP and <125 mmHg in PODCAST) for the secondary prevention of stroke. However, these studies reported a limited number of recurrent stroke events due to relatively small sample sizes and short follow-up durations (PAST-BP: 529 patients for 1 year and PODCAST: 83 patients for 2 years), and neither study was able to demonstrate significant reductions in recurrent stroke incidence associated with strict BP control. In 2019, the results of the RESPECT trial were reported.[38]
The RESPECT study was a randomized trial comparing intensive BP-lowering treatment (target BP <120/80 mmHg) with standard treatment (<140/90 mmHg) in 1280 patients with prior stroke. Although the planned sample size was 2000, this trial was terminated early due to funding cessation by the sponsor. Intensive BP management lowered systolic BP by 6.5/3.3 mmHg and reduced the risks of recurrent stroke by 27% (95% CI: −11% to 51%), although the effect size did not achieve significance (P = 0.15). When the findings of the SPS3, PAST-BP, PODCAST, and RESPECT trials were pooled, however, strict BP control targeting a systolic BP of <120 to 130 mmHg was associated with a significant reduction in the risks of recurrent stroke (relative risk: 0.80, 95% CI: 0.66–0.97), with no evidence of heterogeneity [Figure 4].[35–38]
Figure 4: Meta-analysis of randomized controlled trials of intensive blood pressure lowering for secondary prevention of stroke.
[35–38] Solid boxes represent estimates of hazard ratio; areas of the boxes are proportional to the inverse variance of the estimates; vertical lines represent 95% CI; diamond represents estimate and 95% CI for overall effects. CI: Confidence interval.
Among the 4 trials that investigated the effects of intensive BP-lowering treatments in patients with prior stroke/TIA, 2 trials (SPS3 and RESPECT) conducted subgroup analyses according to age.[35,38] The SPS3 trial demonstrated comparable effects on recurrent stroke for intensive BP-lowering treatments targeting systolic BP <130 mmHg between patients aged <65 years (hazard ratio: 0.76) and those aged ≥65 years (hazard ratio: 0.89). In the RESPECT study, no clear differences were observed for the effects of intensive BP-lowering treatments targeting BP <120/80 mmHg between subgroups defined by age (hazard ratio: 0.93 for patients aged <70 years and 0.57 for those aged ≥70 years, P = 0.260 for the interaction). Currently, no clear evidence has defined different BP targets among older patients with prior stroke/TIA although limited evidence has been presented for very old patients with prior stroke/TIA.
The recently terminated ESH-CHL-SHOT trial, a randomized controlled study investigating optimal BP levels for the secondary prevention of stroke, will soon reinforce the currently available evidence supporting strict BP control among stroke survivors.[39] According to the current guidelines,[29,40–41] BP should be reduced below 140/90 mmHg in all patients during the chronic post-stroke phase and to below 130/80 mmHg when well-tolerated. Due to the limited availability of evidence supporting the efficacy and safety of more intensive BP-lowering regimens, BP should not be reduced beyond 120/70 mmHg, especially among patients with a history of stroke/TIA and coronary heart disease.
Ischemic stroke patients on antithrombotic therapy
Recent clinical practices have resulted in many ischemic stroke patients being placed on antithrombotic drugs. Treatment with antithrombotic drugs increases the risks of hemorrhagic complications, including intracranial hemorrhage.[42] Hypertension is a risk factor for intracranial hemorrhage among patients on antithrombotic drugs, requiring BP management. A subgroup analysis of the PROGRESS trial demonstrated a 46% reduction in the risks of intracranial hemorrhage associated with BP-lowering treatments among 4876 patients receiving antithrombotic drugs.[43] Furthermore, the lowest risks of intracranial hemorrhage were observed among patients who achieved systolic BP levels of 115 mmHg. In the BAT study, a linear association between BP levels and the risks of intracranial hemorrhage was demonstrated, and a BP of 130/81 mmHg was suggested as a cutoff value for the prediction of intracranial hemorrhage occurrence among Japanese patients with cardiovascular or cerebrovascular diseases treated with antiplatelet drugs or warfarin.[44]
The SPS3 trial demonstrated that intensive BP-lowering treatments targeting systolic BP <130 mmHg (compared with standard BP management, targeting systolic BP of 130–149 mmHg) was associated with a 63% reduction in the risk of intracerebral hemorrhage among 3020 patients with symptomatic lacunar infarction receiving antiplatelet therapy (aspirin alone or aspirin + clopidogrel).[35] Based on the evidence above, BP should be lowered to <130/80 mmHg among ischemic stroke patients, as recommended by current Japanese guidelines for the management of hypertension.[29]
Stroke patients with large artery stenosis
A contentious area of BP-lowering treatment during the chronic phase of stroke is the risks and benefits of these therapies among patients with severe large artery stenosis. Among patients with severe stenosis of the extracranial and intracranial large arteries, cerebral perfusion may depend on BP, and strict BP control may induce ischemic stroke due to hemoperfusion. Patients with stenosis in large arteries are also likely to present with atherosclerotic lesions in various large arteries, including coronary, renal, and peripheral arteries; therefore, intensive BP-lowering treatments may result in hypoperfusion and subsequent damage to various organs. The WASID trial conducted an observational analysis to determine the association between BP and ischemic stroke among 567 patients with severe stenosis (50%–99%) of a large artery.[45] Among patients with 50% to 69% stenosis, a linear association was observed between systolic BP and the development of ischemic stroke. Among patients with 70% to 99% stenosis, however, no significant relationship was observed between systolic BP and ischemic stroke. A pooled analysis of the ECST and NASCET trials demonstrated that lower systolic BP was associated with higher stroke risks among patients with ≥70% stenosis in both carotid arteries.[46] Based on these findings, strict BP control might be harmful to patients with severe stenosis on both sides of the cerebral circulation. For high-risk patients, a comprehensive screening of clinical and subclinical atherosclerotic lesions in the coronary, renal, peripheral, carotid, intracranial, and other arteries may be beneficial. In cases in which severe occlusive or stenotic large artery disease is detected, treatment of the arterial lesions should be considered prior to the initiation of strict BP control. Although target BP levels should be defined based on the location and severity of stenosis and other medical conditions in each patient, current Japanese guidelines for the management of hypertension recommend target BP levels of <140/90 mmHg among stroke patients with large artery stenosis.[29] For patients with marked stenosis of the bilateral carotid arteries or the occlusion of a main cerebral artery trunk, very careful BP-lowering strategies are required, and excessive BP reductions should be avoided.
Conclusions
Growing evidence indicates that BP-lowering treatments based on renin-angiotensin system blockers, calcium clockers, and diuretics play effective roles in the prevention of recurrent strokes and other cardiovascular disease manifestations among patients with prior stroke or TIA. Based on current guidelines[29,39–40] and available studies, BP should be lowered below 140/90 mmHg in all patients during the chronic post-stroke phase and below 130/80 mmHg when well-tolerated.
Funding
None.
Conflicts of Interest
None.
Editor note: Hisatomi Arima is an Editorial Board Member of Cardiology Discovery. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and his research groups.
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